Method for preparing colloidal solution of bismuth sodium tartrate

ABSTRACT

A method for preparation of a semitransparent colloidal solution of bismuth sodium tartrate generally comprises producing an aqueous solution of bismuth sodium tartrate; extracting a magma of bismuth sodium tartrate from the aqueous solution at a pH of approximately 2.2; and then dissolving the magma into a salting-in mixture. After addition of preservative and strength testing, the base solution is diluted to elixir strength. The elixir is then buffered to a pH range of about 7.2 to about 7.3 in order to maintain for an extended duration the semitransparent nature of the elixir.

RELATED APPLICATION

The present application is a continuation, under 35 U.S.C. § 120, ofco-pending U.S. patent application Ser. No. 09/547,704 filed Apr. 12,2000. By this reference, the full disclosure, including the claims anddrawings, of U.S. patent application Ser. No. 09/547,704 is incorporatedherein as though now set forth in its entirety.

FIELD OF THE INVENTION

The present invention relates to the preparation of colloidal solutions.More particularly, the invention relates to a method for the preparationof a semitransparent colloidal solution of bismuth sodium tartrate withan extended, stable shelf life.

BACKGROUND OF THE INVENTION

Elixir of bismuth has been known at least since the 1936 NationalFormulary for treatment of various maladies of the gastrointestinaltract, including acid indigestion. According to the 1936 NationalFormulary, elixir of bismuth is produced by diluting a quantity ofglycerite of bismuth and adding further quantities of glycerin andaromatic elixirs as preservative agents. The glycerite of bismuth, asproduced according to the 1936 National Formulary, generally comprises amilky colloidal solution of bismuth sodium tartrate.

Unfortunately, the National Formulary has failed to provide an accuratemethod for testing the strength of the glycerite of bismuth and has alsofailed to suggest methodologies for elimination of aromatic elixirs. Asa result, the elixir of bismuth has to date been difficult andunnecessarily expensive to produce in desired strength.

It is therefore an overriding object of the present invention to improveover the methods of the prior art by presenting a method whereby bismuthsodium tartrate may be produced in a semitransparent colloidal solution,which solution may be accurately and safely tested for strength ofactive ingredient. It is a further object of the present invention topresent such a method wherein the resulting elixir may be expected tohave an extended shelf life. Finally, it is yet another object of thepresent invention to present such a method wherein regulatedingredients, such as aromatic elixirs, may be eliminated from theformula without compromise of product integrity.

SUMMARY OF THE INVENTION

In accordance with the foregoing objects, the present invention—a methodfor preparation of a semitransparent colloidal solution of bismuthsodium tartrate—generally comprises the steps of producing an aqueoussolution of bismuth sodium tartrate; extracting a magma of bismuthsodium tartrate from the aqueous solution at a pH of approximately 2.2;and then dissolving the magma into a salting-in mixture to form thesemitransparent colloidal solution of bismuth sodium tartrate. It iscritical to the present invention that the magma be extracted at a pH ofat least 2.2 but not more than 2.3. As a result, in the preferred methodof the present invention, the magma is extracted by washing with a washliquor comprising an addition of distilled water; allowing the magma tosettle out of the wash liquor; measuring the pH of the wash liquor afterthe magma has settled; and then decanting the wash liquor from themagma. This process is then repeated as necessary to arrive at a magmawithin the critical pH range, whereafter the magma is air dried inpreparation for salting-in.

In the preferred method of the present invention, the salting-insolution is prepared by heating a quantity of distilled water;dissolving a quantity of sodium bicarbonate into the heated quantity ofdistilled water; and then mixing a quantity of tartaric acid with thesolution of sodium bicarbonate and heated distilled water. In thismanner, freezing of the salting-in solution is prevented, therebyensuring a proper mixture.

The preferred method of the present invention further comprises the stepof pasteurizing the semitransparent colloidal solution of bismuth sodiumtartrate in order to eliminate the need for aromatic elixirs withoutcompromise of product purity. In order to prevent damage to the activeingredient, however, the pasteurizing step comprises raising thesemitransparent colloidal solution of bismuth sodium tartrate to atemperature of approximately 54.5° C.; holding the solution at thepasteurization temperature for at least five but not more than eightminutes; and then returning the solution to ambient temperature.

The resulting semitransparent solution may then be tested for strengthutilizing spectral methods. In at least one implementation of thepresent invention, this may comprise the steps of measuring a quantityof light transmitted through a sample of the semitransparent colloidalsolution of bismuth sodium tartrate; converting the measured quantity oflight to an indicium of the density of active ingredient present withinthe solution; and then calculating the per unit quantity of bismuthtrioxide present.

The preferred method of the present invention also comprises dilutingthe base solution to an elixir strength according to the tested strengthof the base. It is critical, however, that the dilute elixir be bufferedto a critical pH range in order to sustain prolonged shelf life withoutdegradation of the semitransparent nature of the product. In particular,sodium bicarbonate is added to the end product to achieve a final pH ofabout 7.2 to 7.3.

Finally, many other features, objects and advantages of the presentinvention will be apparent to those of ordinary skill in the relevantarts, especially in light of the foregoing discussions and the followingdrawings, exemplary detailed description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Although the scope of the present invention is much broader than anyparticular embodiment, a detailed description of the preferredembodiment follows together with illustrative figures, wherein likereference numerals refer to like components, and wherein:

FIG. 1 shows, in flowchart, the first phase of manufacture according tothe preferred method of the present invention of a semitransparentcolloidal solution of bismuth sodium tartrate;

FIG. 2 shows, in flowchart, the second phase of manufacture according tothe preferred method of the present invention of a semitransparentcolloidal solution of bismuth sodium tartrate;

FIG. 3 shows, in flowchart, details of the production of an aqueoussolution of bismuth sodium tartrate as implemented according to thesteps of FIG. 1;

FIG. 4, shows, in flowchart, details of a step in the production of theaqueous solution described in FIG. 3;

FIG. 5 shows, in flowchart, details of the magma extraction process asimplemented according to the steps of FIG. 1;

FIG. 6 shows, in flowchart, a preferred method for production of asalting-in solution utilized according to the steps of FIG. 1;

FIG. 7 shows, in flowchart, details of a pasteurization process asimplemented according to the steps of FIG. 1; and

FIG. 8 shows, in flowchart, details of spectral strength test asimplemented according to the steps of FIG. 1.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Although those of ordinary skill in the art will readily recognize manyalternative embodiments, especially in light of the illustrationsprovided herein, this detailed description is exemplary of the preferredembodiment of the present invention, the scope of which is limited onlyby the claims appended hereto.

As shown in the accompanying Figures, a semitransparent colloidalsolution of bismuth sodium tartrate is preferably formed in two distinctmanufacturing processes—the preparation of a base comprising a glyceriteof bismuth 10, as particularly shown in FIG. 1, and, thereafter, thedilution of the base to an elixir of bismuth 11, as particularly shownin FIG. 2. In the first phase 10 of manufacture, a glycerite of bismuthis generally prepared by producing an aqueous solution of bismuth sodiumtartrate 12, extracting a magma of bismuth sodium tartrate from theaqueous solution 13 and then dissolving the magma into a salting-inmixture 14 to initially form the semitransparent colloidal solution ofbismuth sodium tartrate. The resultant base is then preferablypasteurized 15, for reasons that will be better understood furtherherein, after which a preservative of glycerin may be added 16. Becausethe solution obtained according to the method described herein issemitransparent, spectral techniques may be readily employed to safelytest the base for strength 17 after which it may be placed in bulkstorage until such time as an elixir strength may be desired. In thesecond phase 11 of manufacture, the base formula is diluted to elixirstrength 18, according to the tested strength of active ingredient, andthen prepared for consumer packaging 19, 20, 21.

Although those of ordinary skill in the art will recognize theadjustments necessary to produce other quantities of solutions,especially in light of this exemplary description, the followingdescription specifies the quantities necessary for production ofapproximately 12 gallons of a base of glycerite of bismuth with astrength of 130 mg/ml bismuth trioxide. As will be apparent to those ofordinary skill in the art, this quantity is sufficient to yieldapproximately 100 gallons elixir of bismuth. Although those of ordinaryskill in the art will also recognize that the relative quantities ofactive and/or reactive ingredients are critical to the successfulconduct of the present invention, the absolute values are of coursetypically not critical.

Referring now to FIG. 3, the preferred method for producing the aqueoussolution of bismuth sodium tartrate from bismuth subnitrate 12—a knownstarting material for the active ingredient—is detailed. In the firststep, 8.16 kg of bismuth subnitrate is broken into solution in orderthat further chemical reactions may be effected 22. As known to those ofordinary skill in the art, and as detailed in FIG. 4, this may beaccomplished by mixing 7.24 liters of nitric acid with 11.35 liters ofdistilled water 23 and dissolving the bismuth subnitrate therein 24.After a standing period of approximately 15 minutes to allow operationof the acidic solution on the bismuth subnitrate 25, a further quantityof 26.5 liters of distilled water is added to dilute the volatilesolution to a more safely manageable mixture. At this point, thesolution is agitated to ensure complete breakdown of the bismuthsubnitrate 26. Referring now again to FIG. 3, the broken down solutionof bismuth subnitrate is then reacted with 7.03 kg of tartaric acid NFto form bismuth tartrate 27. Finally, 9.75 kg of sodium bicarbonate USPis added, in small quantities to prevent violent reaction, to thesolution of bismuth tartrate to form the desired aqueous solution ofbismuth sodium tartrate 28. Although the foregoing method is therecognized standard procedure for preparation of bismuth sodium tartratein an aqueous solution, those of ordinary skill in the art willrecognize many possible alternatives. For example, it may be possible tobreak down the bismuth subnitrate with acids other than the verypowerful nitric acid. In any case, all such substantially equivalentmethods should be considered within the scope of the present invention.

In the next steps of manufacture, as shown in FIG. 1, a magma of bismuthsodium tartrate is extracted from the aqueous solution 13 and thendissolved into a salting-in solution to initially form a colloidalsolution of bismuth sodium tartrate 14. Although it is known that themagma of bismuth sodium tartrate must be washed in order to raise its pHto a level safe for handling and fit for consumption, it is critical tothe present invention that the magma of bismuth sodium tartrate beextracted from the aqueous solution at a pH of approximately 2.2 but notgreater than approximately 2.3 in order for the magma to remain soluble.Applicant has discovered that extraction of the magma at a pH greaterthan 2.3 will result in eventual breakdown of the magma—clouding thesemitransparent colloidal solution and in turn preventing theapplication of spectral techniques for strength testing and generallyresulting in a less attractive product for human consumption.

Referring now to FIG. 5, the preferred method for extracting the magmaat the desired pH 13 is detailed. As shown in the Figure, distilledwater is added to the aqueous solution of bismuth sodium tartrate afterwhich the solution is agitated to wash the magma 29. The magma is thenallowed to settle 30 at which time the pH of the wash liquor is tested31. The wash liquor is then decanted from the magma 32 and, so long asthe pH remains below about 2.2, this process is repeated for the furtherelimination of the strong acid remaining therein. In the event the magmais over-washed, as indicated by a measured pH greater than 2.3, thebatch must be aborted 33 and the entire manufacturing process restarted.As a consequence, in order to ensure no product loss, those of ordinaryskill in the art will recognize the necessity for strict process controlduring this phase, including careful adjustment of the quantity ofdistilled water added to the wash. Finally, once the desired pH ofbetween about 2.2 and about 2.3 is obtained, the properly extractedmagma is drained and allowed to dry in preparation for salting-in 34.

As shown in FIG. 6, the salting-in solution comprises a mixture ofsodium bicarbonate USP and tartaric acid NF. Because the chemicalreaction of sodium bicarbonate with tartaric acid causes a dramatictemperature drop, Applicant has found it desirable to preheat a sodiumbicarbonate solution prior to the introduction thereto of the tartaricacid. In this manner freezing of the solution is prevented and acomplete and proper chemical reaction is ensured. In particular,Applicant has found success in raising 11.35 liters of distilled waterto approximately 38° C. in a fifteen gallon stainless steel tank 35.Upon reaching this temperature, 5.44 kg of sodium bicarbonate USP ismixed with the water until completely dissolved 36 whereafter 4.64 kg oftartaric acid NF is added, thereby effecting a clear salting-in solution37. The dry or slightly moist magma of bismuth sodium tartrate may thenbe dissolved into the properly reacted salting-in solution 14. Providedthat the magma was extracted at the specified pH and that a properlyproportioned salting-in solution has been effected, the magma willcompletely dissolve into the salting-in solution to form a substantiallyclear, yellowish colloidal solution of bismuth sodium tartrate.

Because Applicant has found that it is desirable to eliminate aromaticelixirs high in alcohol content in order to reduce government regulationas well as to provide a more palatable and less likely contraindicatedproduct for human consumption, Applicant has introduced a pasteurizationstep 15 in the production of the base solution 10. As a result, the costof production is dramatically reduced through the elimination ofregulatory reporting as well as the ability to use less than chemicallypure tartaric acid. Applicant has found, however, that thepasteurization must be carefully effected in order to ensurepurification of the tartaric acid—particularly the killing of any yeastcontaminant—without damage to the end product as may result from cookingof the sodium bicarbonate. As shown in FIG. 7, the preferred method forpasteurization 15 of the semitransparent colloidal solution comprisesraising the temperature of the solution to approximately 54.5° C. 38,holding the solution at the pasteurization temperature for at least fivebut not more than eight minutes 39, and thereafter cooling the solutionto ambient temperature 40. After the solution is cooled, glycerin q.s.to 45.4 liters is added as a preservative 16.

One particular benefit of producing bismuth sodium tartrate in asemitransparent colloidal solution is that such a solution isparticularly adapted for strength testing by spectral methods. Asdescribed in FIG. 8, such a spectral method may comprise the preparationof a dilute sample 41 through which a light transmission is measured 42.As is known to those of ordinary skill in the art, the measured lighttransmission can then be converted to a density value based uponcalibration tables for the particular spectral instrument being used 43.The resulting density value may then be used to calculate the strengthof the active ingredient 44—in the present case bismuth trioxide, whichstrength may be used in the second phase 11 of manufacture to effect anaccurate dilution of the glycerite of bismuth to an elixir of bismuth18.

Referring now again to FIG. 2, it is preferred that the glycerite ofbismuth be diluted to elixir strength when finally packaged fordistribution to consumers. The dilution is effected, as known to thoseof ordinary skill in the art, in order to obtain the specified dosage ofactive ingredient by volume according to the tested strength of the base18. Coloring and/or flavoring agents may then be added as desired 19.According to the preferred method of the present invention, the solutionis then filtered in accordance with good manufacturing practices toensure elimination of any foreign object as may have been introduced inthe manufacture or storage of the base solution 20.

Finally, Applicant has found that it is critical to package the elixirof bismuth at a pH of at least 7.2 but not more than 7.3 in order toobtain significant shelf life without degeneration of thesemitransparent colloidal solution. Although it is generally known thatthe pH should be neutral or higher to avoid exacerbation of the medicalindication for which the product is used, a pH of approximately 7.3 hasbeen empirically discovered as an upper limit of this rule of thumb.Buffering the end product to a pH above the critical range will resultin the formation over time of undesirable precipitates within thesolution. Because this will result in a product generally unsuitable forordinary consumer markets, care should be observed in obtaining thedesired end pH. According to the preferred method of manufacture, theend pH is obtained by adding sodium bicarbonate USP as necessary toarrive at the critical range 21.

While the foregoing description is exemplary of the preferred embodimentof the present invention, those of ordinary skill in the relevant artswill recognize the many variations, alterations, modifications,substitutions and the like as are readily possible, especially in lightof this description, the accompanying drawings and claims drawn thereto.In any case, because the scope of the present invention is much broaderthan any particular embodiment, the foregoing detailed descriptionshould not be construed as a limitation of the scope of the presentinvention, which is limited only by the claims appended hereto.

1-21. (canceled)
 22. A composition of matter comprising a stable,semitransparent solution of bismuth.
 23. The composition of matter asset forth in claim 22, said solution further comprising an activeingredient.
 24. The composition of matter as set forth in claim 23,wherein said semitransparency is sufficient to allow testing forstrength of said active ingredient.
 25. The composition of matter as setforth in claim 23, wherein said active ingredient comprises bismuthtrioxide.
 26. A stable, semitransparent solution comprising bismuth. 27.The composition of matter as set forth in claim 26, said solutionfurther comprising an active ingredient.
 28. The composition of matteras set forth in claim 27, wherein said semitransparency is sufficient toallow testing for strength of said active ingredient.
 29. Thecomposition of matter as set forth in claim 27, wherein said activeingredient comprises bismuth trioxide.
 30. A stable, semitransparentsolution of bismuth that is fit for human consumption.